Antifungal prodrugs

Abstract

The present invention relates to an antifungal prodrug comprising an antifungal moiety linked to a trigger moiety by means of a self-immolative spacer. The trigger moiety is selected from a glycosyl residue and an oligosaccharide, stabilizing the self-immolative spacer and enabling cleavage by a pathogen hydrolase, preferably an extracellular glycosidase (EC 3.2.1). Upon cleavage of the trigger moiety by the pathogen hydrolase, the self-immolative spacer undergoes spontaneous degradation in order to release the antifungal moiety. The present invention further relates to pharmaceutical compositions comprising the prodrug and to the use thereof in the treatment of infectious diseases.

Description

Technical Field

[0001] This invention relates to the treatment of infectious diseases, particularly fungal and parasitic diseases. Background Technology

[0002] To date, over 300 species of opportunistic fungi capable of infecting humans and animals have been identified. Globally, nearly 1.7 billion people suffer from diseases caused by opportunistic fungal species. Immunocompromised individuals are particularly exposed to very serious infections known as invasive fungal infections (IFIs). Invasive fungal infections refer to the systemic proliferation of opportunistic fungi in a host organism, impairing its survival. IFIs can affect a wide variety of organ systems and include disseminated conditions such as those affecting the lungs, meninges, sinuses, and / or bones. The incidence of IFIs is gradually increasing, primarily due to the growing number of immunocompromised patients, including those with neutropenia, HIV, chronic immunosuppression, indwelling prostheses, burns, and diabetes, as well as those taking broad-spectrum antibiotics. Notably, IFIs cause significant morbidity and mortality in immunocompromised patients: despite current treatment options, IFIs result in death in more than half of infected individuals. The main pathogens involved in IFIs belong to the genera *Candida*, *Aspergillus*, and *Cryptococcus*. To date, there are three main classes of antifungal drugs used to treat invasive fungal infections (IFI): polyene antifungals such as amphotericin B, azole antifungals such as fluconazole or voriconazole, and echinocandins such as caspofungin.

[0003] Among these compounds, amphotericin B is considered the gold standard for antifungal therapy due to its broad spectrum of action and low rate of resistance. Amphotericin B has been shown to be effective in treating fungal infections such as candidiasis, aspergillosis, and cryptococcal infections, as well as severe tropical fungal infections such as blastomycosis and coccidioidomycosis. Amphotericin B is also active against protozoan infections such as leishmaniasis. Amphotericin B was isolated from Streptomyces nodosus culture medium in 1953. Similar to other antifungal polyenes, amphotericin B works by binding to ergosterol, a sterol found in the cell membranes of fungi and protozoa, causing membrane depolarization and leading to pore formation and cell death. Unfortunately, despite its broad spectrum and low rate of resistance, its use in human therapy remains limited to the management of severe, life-threatening infections, particularly in immunocompromised patients, due to its narrow therapeutic window. In fact, amphotericin B causes frequent side effects, with nephrotoxicity being the most serious. Nephrotoxicity encompasses well-known renal tubular damage and can even lead to acute renal failure. Amphotericin B-induced nephrotoxicity is not fully understood and is certainly multifactorial. It involves the high affinity of amphotericin B for cholesterol, which may result in high exposure of renal cells to the drug due to their high expression of lipoprotein receptors. Several strategies have been developed to improve the solubility of amphotericin B (AmB) and / or reduce its adverse side effects.

[0004] The original formulation for intravenous injection was based on a complex of amphotericin B and sodium deoxycholate to improve solubility. Several liposome or lipid complex formulations were then developed to improve the solubility and tolerability of amphotericin B.

[0005] - Lipid complex (ABLC) jointly developed by Enzon Pharmaceuticals and Cephalon, under the trade name Offline sales. AmB is composed of two phospholipids, namely l-α-dimyristoylphosphatidylcholine (DMPC) and l-α-dimyristoylphosphatidylglycerol (DMPG).

[0006] - Developed by Three River Pharmaceuticals laboratories and in the name or The colloidal dispersion system (ABCD) sold below, wherein AmB is compounded with cholesterol sulfate to form a colloidal dispersion system. The drug was discontinued in 2011.

[0007] - Developed by Gilead and Astellas Pharma and under the brand name The liposome formulation (L-AmB) sold below. It consists of a monolayer and a bilayer of liposomes made of phosphatidylcholine, cholesterol and distearate phosphatidylglycerol, in which AmB is inserted into the membrane.

[0008] These formulations have shown lower nephrotoxicity and fewer infusion-related reactions compared to the original formulations. However, their significantly high production costs limit their use in low-income countries. Furthermore, they have other significant drawbacks: It exhibited high clearance and a lower Cmax than the original drug, while Its diffusion in the kidneys and lungs is limited.

[0009] The solubility of AmB has also been improved through chemical modification. For example, Sedlak et al. (Bioorganic & Medicinal Chemistry Letters, 2001, 11, 2833-2835) described the synthesis of AmB-polyethylene glycol (PEG) conjugates. These conjugates showed enhanced solubility in water, but a significant reduction in antifungal activity compared to free AmB was observed by in vitro bioassays (Tan et al., 2016, PLOS ONE | DOI: 10.1371 / journal.pone.0152112). Conjugates with other structures such as β-calix[4]arenes (Paquet et al., Bioconj. Chem, 2006, 1460-3) and dialkylated AmB derivatives with amino groups (WO2007096137) have also been described.

[0010] However, there remains a demand for new derivatives of antifungal drugs that offer improved solubility, improved distribution, better site-of-infection targeting, and / or fewer side effects compared to currently available antifungal drugs. Summary of the Invention

[0011] This invention relates to an antifungal prodrug of formula (A):

[0012]

[0013] in

[0014] -AFD refers to antifungal drugs.

[0015] -SIS refers to a self-immolative spacer covalently bound to AFD and TM, and

[0016] -TM refers to the triggering component, selected from glycosyl residues and oligosaccharides, which stabilizes the SIS and allows it to be cleaved by pathogen hydrolases, preferably extracellular glycosidases (EC 3.2.1).

[0017] When TM is cleaved by the pathogen hydrolytic enzyme, SIS undergoes spontaneous degradation in order to release AFD.

[0018] In some embodiments, the antifungal prodrug of formula (A) is as follows:

[0019] -TM is selected from autoglycoamine, N-acetylhexylamine, neuraminic acid, sialic acid, and oligosaccharides comprising 2 to 50, preferably 2 to 10, glycosyl residues, and / or

[0020] -AFD is selected from azole antifungal drugs, polyene antifungal drugs, echinocandins, orotomides, and acetamipridin agarose glycoside derivatives.

[0021] In some embodiments, TM is selected from glucosamine, galactosamine, mannosamine, neuraminic acid, N-acetylglucosamine, N-acetylgalactosamine, sialic acid, N-acetylmannosamine, and chitin. For example, TM is N-acetylglucosamine or N-acetylgalactosamine.

[0022] In some other embodiments, the AFD is selected from amphotericin B, nystatin, natamycin, caspofungin, micafungin, anidofungin, rezafungin, voriconazole, ketoconazole, itraconazole, fluconazole, olorofim, and their derivatives.

[0023] In a preferred embodiment, AFD is caspofungin, voriconazole, or amphotericin B, more preferably amphotericin B.

[0024] In some embodiments of the prodrug of the present invention, the SIS is selected from self-degrading spacers that undergo spontaneous degradation involving electronic cascades or cyclization. For example, the SIS may comprise or be constituted by components of or of formula (Ia1), (Ib1), (Ic1), or (Id1):

[0025]

[0026] in

[0027] -X is O, S, -O(C=O)-NH-, O(C=O)O-, -O(P=O)O-, -O(P=S)O-, or NR, wherein R is H or a C1-C3 alkyl group, preferably CH3.

[0028] -R1 is H, a halogen such as F, Br or Cl, -NO2, C1-C3 alkyl, -CF3-NHR, -OR, -C(=O)OR, -SO2R, wherein R is H or C1-C3 alkyl, preferably CH3, or a targeted component, and

[0029] -R3 is an H or target component, and

[0030] -R1 and R3 are not simultaneously components of the target.

[0031] Preferably, R3 is H, and R1 is H, halogen, -NO2, -CF3, -OR, -C(=O)OR, -SO2R, wherein R is H or C1-C3 alkyl, preferably CH3.

[0032] In a particular embodiment, the antifungal prodrug of formula (A) is selected from compounds of formula (A2) and their pharmaceutically acceptable salts:

[0033]

[0034] in:

[0035] -TM is a glycosyl residue selected from glucosamine, galactosamine, N-acetylglucosamine, N-acetylglucosamine, mannosamine, neuraminic acid, and sialic acid;

[0036] -AFD is an antifungal drug selected from amphotericin B, nystatin, natamycin, caspofungin, micafungin, anidofungin, rezafungin, voriconazole, ketoconazole, itraconazole, fluconazole and their derivatives, preferably selected from amphotericin B, caspofungin and voriconazole.

[0037] Examples of the antifungal prodrug of the present invention are:

[0038]

[0039] Or its medicinal salt.

[0040] This invention also relates to the use of antifungal prodrugs as defined above for the treatment or prevention of infectious diseases. These infectious diseases can be caused by pathogens belonging to the genera *Candida*, *Aspergillus*, *Cryptococcus*, *Mucorales*, *Fusarium*, *Scedosporium*, *Lomentospora*, *Blastomyces*, *Mucorales*, or the genera *Leishmania*, *Trypanosoma*, and *Plasmodium*. The antifungal prodrugs are particularly useful for the treatment or prevention of invasive fungal diseases in immunocompromised subjects.

[0041] The present invention also relates to a pharmaceutical composition comprising an antifungal prodrug as defined above and a pharmaceutically acceptable excipient.

[0042] The present invention also relates to a method for treating or preventing infectious diseases in a subject, the method comprising administering, preferably orally or intravenously, an effective amount of an antifungal prodrug as defined herein.

[0043] The present invention also relates to the use of the antifungal products described herein in the preparation of pharmaceutical compositions for the treatment or prevention of infectious diseases, preferably for oral or intravenous administration. Attached Figure Description

[0044] Figure 1A The AmB prodrug of the present invention is shown. This compound provides proof of concept for the invention and is evaluated in the Examples section of this application.

[0045] Figure 1B The mechanism of AmB release from the prodrug is illustrated, which includes the hydrolysis of the target component by fungal hydrolytic enzymes and the subsequent spontaneous degradation of the self-decomposing spacer.

[0046] Figure 2 The synthetic route and reaction conditions for preparing AmB precursor drugs are shown.

[0047] Figure 3 The kinetics of AFD release from AmB prodrug incubated with β-N-acetylhexosaminease are shown. Figure 1B The kinetics of intermediate 3 and residue 5 are shown in the figure. Notably, the AmB prodrug is stable in an aqueous medium at 37°C (in the absence of enzymes).

[0048] Figure 4a shows the survival rates of different animal groups in a mouse model infected with Candida albicans budding conidia, where group (i) was used Treatment, (ii) with Treatment, (iii) with the AmB prodrug of the present invention ( Figure 1A (iv) Treatment with the compound referred to herein as GOG, and administration via a medium (control).

[0049] Figure 4B The image shows the fungal load in the kidneys of different groups in a mouse model infected with Candida albicans bud conidia, determined after euthanasia. Group (i) of the animals was... Treatment, (ii) with Treatment, (iii) with the AmB prodrug of the present invention ( Figure 1A (iv) Treatment with the compound referred to herein as GOG, and administration via a medium (control).

[0050] Figure 5AThe invention demonstrates the use of amphotericin B (AmB) and the AmB prodrug of the present invention (…). Figure 1A Survival curves of the compound and the control treatment (G. melonella) were compared.

[0051] Figure 5B The invention demonstrates the use of amphotericin B (AmB) and the AmB prodrug of the present invention (…). Figure 1A Survival curves of G. melonella infected with Cryptococcus neoformans and control treatment of the compound) and control treatment. Detailed Implementation

[0052] The inventors have conceived a novel prodrug of amphotericin B that exhibits improved solubility, biodistribution, tolerability, and better site-of-infection targeting compared to amphotericin B. This novel prodrug is based on a carrier platform that enhances solubility, masks the toxicity of fungal drugs, and facilitates the release of the active drug at very precise sites of infection.

[0053] This carrier platform is based on a triggering component linked to an antifungal drug via a self-degrading group. The triggering component stabilizes the self-degrading group and is selectively recognized and cleaved by hydrolytic enzymes spontaneously secreted by the pathogen at the site of infection. Following cleavage by the triggering component, the self-degrading group spontaneously undergoes rearrangement, resulting in the release of the active antifungal drug.

[0054] Therefore, the carrier platform conceived by the inventors utilizes the fact that pathogens, such as fungi, spontaneously secrete hydrolytic enzymes at the site of infection. Selecting a triggering component specifically targeting the hydrolytic enzymes secreted by the pathogen enables precise restriction of the release of the antifungal drug to the site of fungal infection, while preventing damage to the patient's cells, thereby limiting side effects.

[0055] The inventors utilized AmB to provide a proof-of-concept for their innovative carrier platform. They conceived of a... Figure 1A The AmB prodrug shown here, wherein the carrier platform is linked to the amino group of mycosamine and contains N-acetylglucosamine as a triggering component and 4-hydroxy-3-nitrobenzyl alcohol as a self-decomposing group.

[0056] As described in the Examples section, the inventors have demonstrated that AmB is rapidly released from the prodrug following action by β-N-acetylhexosaminease.

[0057] As in Figure 1B The explanation in and in Figure 2As shown, the hydrolase efficiently cleaves the triggering component, namely the N-acetylglucosamine group, leading to the release of intermediate 3. Intermediate 3 spontaneously undergoes rearrangement, releasing the active drug AmB.

[0058] It is worth noting that the prodrug has been shown to be stable in aqueous buffer at 37°C without undergoing any significant hydrolysis.

[0059] The inventors then evaluated the antifungal activity of the prodrug against different fungal cell types, namely budding spores and filamentous yeasts, as well as Leishmania proflagellates and intracellular aflagellates. Notably, the prodrug showed the same efficacy as AmB against these different cell types, confirming the efficient release of AmB from the prodrug through the action of pathogen hydrolytic enzymes.

[0060] Furthermore, the prodrug did not exhibit any significant toxicity to HELA cells, whereas AmB had an IC50 of approximately 23 μM. Therefore, the prodrug is not metabolized by human cells and has no significant toxicity to human cells.

[0061] The inventors have also demonstrated that, for treating fungal infections in a mouse model infected with Candida albicans bud conidia, the AmB prodrug of this invention is effective against... (AmB) and (The liposomal formulation of AmB) is at least as effective. Notably, the group treated with the AmB prodrug of the present invention showed a significant improvement in survival and a significant reduction in renal fungal load compared to the control group.

[0062] The inventors also investigated the effects of AmB and the AmB precursor of the present invention on the large wax moth (Galleria mellonella) model, a larval model capable of assessing the efficacy and inherent toxicity of active drugs. The inventors showed that the AmB precursor of the present invention was significantly less toxic than AmB, confirming the data obtained in human cell lines.

[0063] Furthermore, in the Galleria melonella model, the AmB precursor drug showed efficacy against Cryptococcus neoformans and Cryptococcus cragiti infections on the same order of magnitude as AmB.

[0064] In summary, these results strongly support the fact that the carrier platform conceived by the inventors does not impair the antifungal activity of the drug, improves its solubility, and promotes its specific release near the site of infection, while preventing adverse side effects caused by the excessive diffusion of antifungal agents. This thus increases the therapeutic window of the antifungal drug.

[0065] Without being limited by any theory, the inventors believe that this carrier platform for AmB can also be effectively used for the carrier of other antifungal drugs such as echinocandins.

[0066] Therefore, the present invention relates to an antifungal prodrug of formula (A):

[0067]

[0068] in

[0069] -AFD refers to antifungal drugs.

[0070] -SIS refers to a self-decomposing spacer covalently bound to AFD and TM, and

[0071] -TM refers to the triggering component, which stabilizes the SIS and enables it to be cleaved by pathogen hydrolytic enzymes.

[0072] When TM is cleaved, SIS undergoes spontaneous degradation in order to release AFD.

[0073] Therefore, the active AFD is released from the prodrug of the present invention through a two-step process, the process comprising (i) enzymatic hydrolysis of the covalent bond between TM and SIS, and (ii) spontaneous degradation of SIS.

[0074] - Antifungal drugs (AFD)

[0075] When used herein, an antifungal drug (AFD) means any drug that has fungicidal or antifungal activity against at least one pathogenic fungal species. In some embodiments, the antifungal drug acts on at least one pathogenic fungus belonging to the genera *Candida*, *Aspergillus*, and *Cryptococcus*. In certain embodiments, the antifungal drug has broad-spectrum activity, meaning that it exhibits antifungal activity against a variety of fungal species.

[0076] The antifungal drugs typically have a concentration of less than 2000 g / mol. -1 Preferably less than 1500 g·mol⁻¹ -1 The molecular weight.

[0077] Antifungal drugs include, but are not limited to, azole antifungals, polyene antifungals, echinocandins, orotomides, and acetamiprid glycoside derivatives.

[0078] When used herein, azole antifungal agents refer to antifungal compounds comprising at least one 5-membered heterocyclic component containing a nitrogen atom and at least one additional non-carbon atom (i.e., nitrogen, sulfur, or oxygen) as part of the ring. Preferred heterocycles are triazoles and imidazoles. Zazole antifungal agents work by inhibiting lanosterol 14α-demethylase to block the conversion of lanosterol to ergosterol. Zazole antifungal agents include, but are not limited to, ketoconazole, itraconazole, fluconazole, irfluconazole, abaconazole, voriconazole, ravuconazole, and posaconazole.

[0079] The azole antifungal drug may, for example, be linked to the self-degrading spacer (SIS) via its hydroxyl group (if present).

[0080] When used herein, a polyene antifungal agent (also referred to herein as a polyene antibiotic or polyene antifungal agent) means an antifungal drug comprising a macrocycle containing densely packed hydroxylated regions opposite regions containing multiple conjugated double bonds (polyene components). The macrocycle of a polyene antifungal agent typically carries an aminoglycoside such as D-trehaloseamine.

[0081] Polyene antifungal drugs typically act as ion carriers. They bind to ergosterol, a major component of fungal cell membranes, and create pores in the membrane, leading to K+ leakage, acidification, and fungal death.

[0082] Polyene antifungal drugs include, but are not limited to, amphotericin A and B, nystatin and natamycin, rezafungin, sclerotinib, ferulic acid, haramicin and epimycin.

[0083] When the antifungal drug (AFD) is a polyene antifungal agent containing an aminoglycoside group, the AFD is preferably linked to the self-degrading spacer (SIS) via the amino group of the aminoglycoside. In other cases, the AFD may be linked to the SIS via one of the hydroxyl groups present on the macrocycle.

[0084] When used herein, echinocandins refer to macrocyclic lipopeptide antifungal drugs that act by inhibiting the enzyme (1→3)-β-D-glucan synthase and thus disrupting the integrity of the fungal cell wall. Echinocandins typically contain a lipophilic tail linked to the peptide macrocycle. Echinocandins include, but are not limited to, caspofungin, micafungin, anifungin, rezafungin, echinocandin B (also known as CD 101–CAS N°1396640-59-7), nimocontin B0, biafungin, and aminocontin. When the AFD is an echinocandin, it can be linked to the SIS via one of its free hydroxyl or amino groups, preferably via one of its primary amino groups (if present).

[0085] As alternatives to echinocandins, acephate-gold glycoside derivatives such as irifenine (also known as SCV 078 and MK 3118) can be used. Similar to echinocandins, these compounds are inhibitors of fungal β-1,3-D-glucan synthase. Irifenine is a novel antifungal drug under development (Phase III clinical trials are ongoing). Its CAS number is 1207753-03-04. Other acephate-gold glycoside derivatives of interest are disclosed in patent application WO2010019203.

[0086] When used herein, orotomides refer to a new class of antifungal agents containing pyrrole components and acting by stopping pyrimidine biosynthesis in fungal cells. Orotomides cause reversible inhibition of dihydroorotate dehydrogenase (DHODH). This inhibition, in turn, blocks hyphal growth.

[0087] Orotomides of interest are described, for example, in patent application WO2016079536. A preferred orotomide is orofim (CAS No. 1928707-56-5), which is currently in Phase III clinical trials.

[0088] When used in this document, “derivative” means any AFD that contains one or more chemical modifications while retaining its antifungal activity.

[0089] In some embodiments, the AFD is selected from amphotericin B, nystatin, natamycin, caspofungin, micafungin, anidofungin, rezafungin, voriconazole, ketoconazole, itraconazole, fluconazole, olorofim, and their derivatives.

[0090] - Self-decomposing spacers (SIS)

[0091] Self-degrading spacers (SIS) (also referred to herein as self-degrading groups) are chemical groups that link an antifungal drug (AFD) and a triggering component (TM) together and undergo spontaneous decomposition after the TM is cleaved.

[0092] In fact, when the triggering component (TM) is released, i.e. when the covalent bond between TM and SIS is cleaved by the action of pathogen hydrolytic enzymes, SIS spontaneously undergoes structural rearrangement, resulting in the release of the active antifungal drug at the site of infection.

[0093] The SIS was selected to enhance the solubility of AFD and / or limit steric hindrance around TM, enabling TM to be recognized by the hydrolytic enzyme of interest. The SIS was also selected to rapidly decompose TM after it is cleaved by fungal hydrolytic enzymes, thereby releasing AFD.

[0094] SIS can be a bifunctional or trifunctional spacer. When using a trifunctional SIS, the SIS carries another entity, such as an additional AFD component, a component for improving solubility such as a PEG component, or a targeting component as further defined below.

[0095] Self-decomposing groups are well known in the art and have been extensively studied. See Schmidt et al., Angew. Chem. Int., 2015, 54, 7492-7509, for a review of self-decomposing spacers, the contents of which are incorporated herein by reference.

[0096] As explained by Schmidt et al., the spontaneous decomposition of self-decomposing groups is primarily driven by two types of processes: (i) electronic cascades, which can lead to the formation of quinones or azaquinones, and (ii) cyclization, which can produce imidazolidine ketones, Azoxyliquidone or 1,3-oxothionecyclopentane-2-one ring structure.

[0097] In some embodiments, the self-decomposing spacer decomposes by electronic cascade and contains an aromatic structure with O-, N-, or S- groups.

[0098] In certain implementations, the SIS includes or is composed of components of formulas (Ia), (Ib), (Ic), or (Id):

[0099]

[0100] in

[0101] -X is O, S, -O(C=O)-NH-, O(C=O)O-, -O(P=O)O-, -O(P=S)O-, or NR, wherein R is H or a C1-C3 alkyl group, preferably CH3.

[0102] -R1 is H, a halogen such as F, Br or Cl, -NO2, C1-C3 alkyl, -CF3-NHR, -OR, -C(=O)OR, -SO2R, wherein R is H or C1-C3 alkyl, preferably CH3, or a targeted component, and

[0103] -R3 is H or a target component.

[0104] R1 can be located at the para, meta, or ortho position of the X group. Preferably, R1 is located at the ortho or para position. Preferably, R1 and R3 are not simultaneously target components.

[0105] When used herein, "targeting component" means any group capable of delivering the prodrug to a specific organ, tissue, or cell of a subject or to a specific pathogen. The targeting component can be of any type. Typically, the targeting component is capable of specifically binding to a target component expressed in the organ, tissue, cell, or pathogen to be targeted.

[0106] For example, the target component can be selected from antibodies, antibody fragments or derivatives such as Fab, Fab', and ScFv, aptamers, spikelers, peptide aptamers, and ligands or substrates of the target component of interest. The ligands or substrates can be of any type, for example, with a molecular weight less than 1000 g·mol⁻¹. -1 Small chemical molecules, peptides, sugars, hormones, oligosaccharides, proteins, and receptors or receptor fragments that can bind to target components.

[0107] The target component may be, for example, a membrane protein such as a membrane receptor, a membrane or cell wall component, etc. In a particular embodiment, the target component is a component of the pathogen cell wall or a component present on the pathogen surface, such as an external fragment of Asl3 (lectin-like protein 3), HWP1 (filament protein 1), β-D-glucan, or HSP90 (heat shock protein 90).

[0108] Therefore, the target can be Asl3, HWP1, HSP90, or β-D-glucan. In some embodiments, the target component includes spacers capable of covalently binding to the core structure of the SIS while simultaneously limiting steric hindrance and / or improving solubility. For example, the spacers can be hydrophilic spacers, such as PEG-based spacers.

[0109] In certain implementations, SIS is a component of formula (Ia1), (Ib1), (Ic1), or (Ia1):

[0110]

[0111] X, R1, and R3 are defined as above.

[0112] In a particular implementation, the SIS includes or is composed of the formula (Ib2):

[0113]

[0114] R1 is as defined above. In a preferred embodiment, R1 is selected from H, halogens such as F, Br or Cl, -NO2, -CF3, -C(=O)OR, and -SO2R, wherein R is H or a C1-C3 alkyl group, preferably CH3. R1 can be in the ortho or para position, preferably in the ortho position.

[0115] In some other embodiments, the self-decomposing spacer relies on a cyclization mechanism and comprises an alkyl chain and / or an aromatic component. For example, the self-decomposing spacer may comprise or be composed of components of formula (Ie), (If), (Ig), (Ih), or (Ii):

[0116]

[0117] in:

[0118] -X1 is CH2, O, S, or NR, where R is H or a C1-C3 alkyl group, preferably CH3.

[0119] -Y1 is CH2, O, NH or a single bond.

[0120] -R2 is H, a halogen such as F, Br or Cl, -NO2, C1-C3 alkyl, -CF3-NHR, -OR, -C(=O)OR, -SO2R, where R is H or C1-C3 alkyl, preferably CH3, or a targeted component, and

[0121] -n is an integer from 1 to 5, preferably 1 or 2.

[0122] As mentioned above, the prodrug may contain a targeting component typically carried by the self-degrading spacer. The self-degrading spacer may be a trifunctional linker that combines the TM, AFD, and the targeting component. Such self-degrading spacers, also known as chemical linkers, are described, for example, in Gopin et al., Bioorg. Med. Chem. 2004, 12, 1853-1858 and Gopin et al., Angew. Chem. Int. Ed. 2003, 42, 327-332.

[0123] For example, a SIS can contain or be composed of components of formula (Ij) or (Ik):

[0124]

[0125] TargM is the target component as defined above.

[0126] In certain implementations, the SIS includes or is composed of components of formula (Ib3):

[0127]

[0128] R1 is as defined above, and R3 is H or a target component (TargM).

[0129] Preferably, R1 is selected from H, halogens such as F, Br or Cl, -NO2, -CF3, -C(=O)OR and -SO2R, wherein R is H or C1-C3 alkyl, preferably CH3.

[0130] Therefore, the prodrug of the present invention can be a compound of formula (A1):

[0131]

[0132] R1 is as defined above, and R3 is H or a target component, preferably H.

[0133] In a specific embodiment, R3 is H, and R1 is NO2. Therefore, the prodrug is a compound of formula (A2):

[0134]

[0135] - Triggering Components (TM)

[0136] When used herein, the triggering component (TM) refers to a chemical group that stabilizes the SIS, i.e., prevents its spontaneous degradation and thus acts as a protecting group. In the context of this invention, the TM is selected to be selectively cleaved by the action of an enzyme expressed by the pathogen of interest. The enzyme of interest is a pathogen hydrolase, such as a fungal hydrolase secreted into the extracellular environment and capable of catalyzing the release of glycosyl components from the substrate of interest.

[0137] For example, the pathogen hydrolytic enzyme is an extracellular glycosidase (EC3.2.1) capable of catalyzing the hydrolysis of O-, N-, or S-glycosides. Hydrolases of interest include, but are not limited to, β-N-acetylhexosaminease (EC 3.2.1.52), β-N-acetylgalactosaminease (EC 3.2.1.53), chitinase (EC 3.2.1.14), β-glucosidase (EC 3.2.1.21), α-D-mannosidase (EC 3.2.1.24), β-D-mannosidase (EC 3.2.1.25), chitobiosease (EC 3.2.1.29), β-D-acetylglucosaminease (EC 3.2.1.30), exo-α-sialidase (EC 3.2.1.18), endo-α-sialidase (EC 3.2.1.129), and exo-1,4-β-D-glucosaminease (EC 3.2.1.165).

[0138] Therefore, the triggering component is typically a glycosyl group. In some embodiments of the invention, the triggering component is selected from autosaccharides and N-acetylhexylamine, preferably N-acetylhexylamine. The trigger may also be selected from 9-carbon sugars such as neuraminic acid and sialic acids such as N-acetylneuraminic acid.

[0139] The triggering component may also be selected from oligosaccharides based on hexanoamine or N-acetylhexanoamine, such as chitin, and / or oligosaccharides based on neuraminic acid or sialic acid. Typically, the oligosaccharide may contain 2 to 50 glycosyl residues, for example, 2 to 10 glycosyl residues.

[0140] When used herein, hexosamine refers to a hexose in which one of the hydroxyl groups has been replaced by an amino group. Hexosamines include, but are not limited to, fructosamine, galactosamine, glucosamine, and mannosamine.

[0141] In some embodiments, the triggering component (TM) is selected from glucosamine, galactosamine, mannosamine, N-acetylglucosamine, N-acetylglucosamine, N-acetylglucosamine, N-acetylglucosamine, chitin, neuraminic acid, and sialic acid.

[0142] In other embodiments, TM is selected from N-acetylglucosamine, N-acetylglucosamine, N-acetylgmannosamine, and sialic acid components. For example, the triggering component is N-acetylglucosamine or N-acetylglucosamine. Such glycosyl residues can be cleaved by fungal β-N-acetylhexosaminease (EC 3.2.1.52).

[0143] - Examples of compounds according to the invention

[0144] In some embodiments, the prodrug of the present invention is a compound of formula (A) or a pharmaceutically acceptable salt thereof:

[0145]

[0146] in

[0147] -TM is an oligosaccharide containing 2 to 50, preferably 2 to 10, glycosyl residues of autoglycoamine, N-acetylhexylamine, neuraminic acid, or sialic acid.

[0148] -SIS is a component of or composed of formulas (Ia), (Ib), (Ic), (Id), (Ij), or (Ik), and a self-decomposing spacer thereof.

[0149] -AFD is an antifungal drug selected from azole antifungals, polyene antifungals, echinocandins, orotomides, acetamiprid glycoside derivatives and their derivatives.

[0150] In some other embodiments, the prodrug of the present invention is a compound of formula (A), wherein:

[0151] -TM is a glycosyl residue selected from glucosamine, galactosamine, mannosamine, N-acetylglucosamine, N-acetylglucosamine, N-acetylglucosamine, N-acetylglucosamine, neuraminic acid, and chitin.

[0152] -SIS is a component of or composed of (Ia1), (Ib1), (Ic1), (Id1), (Ib2), or (Ib3), and a self-decomposing spacer thereof.

[0153] -AFD is an antifungal drug selected from amphotericin B, nystatin, natamycin, caspofungin, micafungin, anidofungin, rezafungin and their derivatives.

[0154] In some embodiments, the prodrug is a compound of formula (A), wherein:

[0155] -TM is a glycosyl residue selected from glucosamine, galactosamine, mannosamine, N-acetylglucosamine, N-acetylgalactosamine, and N-acetylmannosamine residues.

[0156] -SIS is a self-decomposing spacer.

[0157] -AFD is an antifungal drug selected from amphotericin B, caspofungin and its derivatives.

[0158] An SIS may contain or be composed of any of the formulas (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ij), or (Ik).

[0159] In some other embodiments, the prodrug of the present invention is a compound of formula (A), wherein:

[0160] -TM represents N-acetylglucosamine residues and N-acetylglucosamine residues, preferably N-acetylglucosamine residues.

[0161] -SIS is a self-decomposing spacer.

[0162] -AFD is an antifungal drug selected from amphotericin B, caspofungin and its derivatives.

[0163] SIS may include, preferably be a component of, or be composed of any of the formulas (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih1), (Ih2), (Ij), (Ik), (Ib2), and (Ib3).

[0164] In some preferred embodiments, AFD is amphotericin B.

[0165] In other embodiments, the prodrug of the present invention is a compound of formula (A1) or a pharmaceutically acceptable salt thereof, wherein:

[0166]

[0167] in

[0168] -R1 is H, a halogen such as F, Br or Cl, -NO2, a C1-C3 alkyl group, -CF3-NHR, -OR, -C(=O)OR, -SO2R, where R is H or a C1-C3 alkyl group such as CH3.

[0169] -R3 is H or a target component, preferably H.

[0170] -TM is a glycosyl residue selected from glucosamine, galactosamine, mannosamine, N-acetylglucosamine, N-acetylgalactosamine, and N-acetylmannosamine, and

[0171] -AFD is an antifungal drug selected from polyene antifungal drugs and echinocandins such as amphotericin B, nystatin, natamycin, caspofungin, micafungin, anidoxin, rezafungin, voriconazole, eriofenamic acid, olorofim and their derivatives.

[0172] In another embodiment, the prodrug of the present invention is a compound of formula (A1) or a pharmaceutically acceptable salt thereof, wherein:

[0173] -R1 is H, a halogen such as F, Br or Cl, -NO2, -CF3, -NHR, -C(=O)OR, -SO2R, where R is H or a C1-C3 alkyl group such as CH3.

[0174] -R3 is H,

[0175] -TM is a glycosyl residue selected from glucosamine, galactosamine, N-acetylglucosamine, and N-acetylglucosamine.

[0176] -AFD is an antifungal drug selected from polyene antifungal drugs, echinocandins, orotomides, and acetamiprid glycoside derivatives such as amphotericin B, nystatin, natamycin, caspofungin, micafungin, anisofungin, rezafungin, voriconazole, eriofen, olorofim, and their derivatives.

[0177] In another embodiment, the prodrug of the present invention is a compound of formula (A2) or a pharmaceutically acceptable salt thereof.

[0178]

[0179] in:

[0180] -TM is a glycosyl residue selected from glucosamine, galactosamine, N-acetylglucosamine, and N-acetylglucosamine.

[0181] -AFD is an antifungal drug selected from polyene antifungal drugs, echinocandins, azole antifungal drugs, orotomides, and amphotericin B, nystatin, natamycin, caspofungin, micafungin, anidoxuridine, rezafungin, voriconazole, ketoconazole, itraconazole, fluconazole, irifenazole, Olorofim, and their derivatives.

[0182] In another embodiment, the prodrug of the present invention is a compound of formula (A3) or a pharmaceutically acceptable salt thereof:

[0183]

[0184] - Wherein R1 is selected from H, -NO2, -COOMe, preferably -NO2, and AFD is selected from polyene antifungal drugs, echinocandins, azole antifungal drugs and their derivatives, preferably selected from amphotericin B, nystatin, natamycin, caspofungin, micafungin, anidofungin, rezafungin, voriconazole and their derivatives.

[0185] Preferably, the AFD is voriconazole, amphotericin B, and caspofungin, more preferably amphotericin B.

[0186] For example, the prodrug of the present invention may be one of the following compounds or a pharmaceutically acceptable salt thereof:

[0187]

[0188] When used herein, the term "pharmaceutical-grade salt" refers to a non-toxic salt that is typically prepared by contacting a prodrug of interest (e.g., an AmB prodrug) with a suitable organic or inorganic acid. For example, pharmaceutical-grade salts can be, but are not limited to, acetates, benzenesulfonates, benzoates, bicarbonates, bisulfates, tartrates, bromides, butyrates, carbonates, chlorides, citrates, diphosphates, fumarates, iodides, lactates, laurates, malates, maleates, mandelates, methanesulfonates, oleates, oxalates, palmitates, phosphates, propionates, succinates, sulfates, tartrates, etc.

[0189] The prodrugs of this invention can be prepared using standard chemical methods. The Examples section describes the synthesis of specific prodrugs of this invention, which can be adapted to obtain other prodrugs of interest.

[0190] - Therapeutic uses and methods of the present invention

[0191] This invention also relates to the use of the prodrug as defined above in the treatment or prevention of infectious diseases. Another object of this invention is a method for treating or preventing an infectious disease in a subject, the method comprising administering an effective amount of the prodrug of the invention to the subject. This invention also relates to the use of the prodrug of the invention for the treatment or prevention of infectious diseases in a subject.

[0192] When used herein, "infectious disease" (also referred to herein as infection) means any disease or disorder and its symptoms caused by or resulting from contamination of a subject by a pathogen such as pathogenic bacteria, fungi including yeasts and molds, or protozoa or viruses. In a preferred embodiment, the infectious disease is caused by pathogenic fungi such as pathogenic yeasts or molds or pathogenic protozoa, more preferably pathogenic fungi.

[0193] For example, the infectious disease can be caused by pathogens belonging to the genera Candida, Aspergillus, Cryptococcus, Mucorales, Fusarium, Scedosporium, Lomentospora, Blastomyces, or Leishmania, Trypanosoma, Plasmodium.

[0194] Examples of pathogens include Aspergillus fumigatus, Aspergillus flavus, Candida albicans (including Candida albicans bud conidia), Candida krusei, Candida lusitaniae, Candida parapsilosis, Candida tropicalis, Candida glabrata, Candida Auris, Cryptococcus neoformans, Cryptococcus gattii, and Blastomyces dermatitidis.

[0195] The infectious disease may be systemic, involving one or more organs such as organ systems like the respiratory or gastrointestinal tract, or it may be localized, i.e., limited to a specific organ or tissue such as the brain, skin, or mouth. The infectious disease may be a mucosal infection such as an oral, esophageal, or vaginal infection, or an infection affecting the subject's bones, skin, blood, genitourinary tract, or central nervous system; this list is not exhaustive.

[0196] The infectious diseases mentioned include, but are not limited to, infections caused by Candida albicans, Aspergillus, Cryptococcus, Mucor, blastomycosis, Fusarium, and Leishmaniasis.

[0197] In some implementations, the infectious disease can be a hospital-acquired infection (i.e., iatrogenic infection) or a community-acquired infection.

[0198] In some implementations, the infectious disease is an invasive fungal disease (IFD).

[0199] Subjects treated with the prodrug of the present invention are preferably mammals, more preferably humans. The subjects can be of any sex and any age, including newborns, infants, children, and elderly subjects.

[0200] In some embodiments, the subject is immunocompromised. The patient's immunocompromised state may be primary immunodeficiency (i.e., congenital or hereditary deficiency) or secondary immunodeficiency, such as that caused by surgery or immunosuppressive treatments like chemotherapy and anti-rejection drugs, cancers like leukemia, pathogens like the human immunodeficiency virus (HIV) that causes AIDS, and autoimmune diseases. In some embodiments, the subject may have a disease that makes him susceptible to infectious diseases. For example, the patient may have diabetes.

[0201] In some other embodiments, the patient has undergone or will undergo surgery. In this case, the prodrug of the present invention can be used to prevent the onset of an infectious disease in a subject who has undergone or will undergo surgery. The prodrug of the present invention can also be used to prevent infectious diseases as described above in subjects exposed to pathogens. For example, the subject may be a healthcare worker.

[0202] In certain circumstances, the prodrug of the present invention may be administered to a subject in combination with another therapeutic agent. The administration of the other therapeutic compound and the administration of the prodrug of the present invention may be simultaneous, separate, or sequential.

[0203] When used herein, "therapeutic effective amount" means the amount of the prodrug used in a subject, preferably a human, to prevent, eliminate, slow down an infectious disease, or alleviate or delay one or more symptoms or disorders caused by or associated with the infectious disease.

[0204] The effective amount and, more generally, the dosage regimen of the prodrug and pharmaceutical composition of the present invention can be readily determined and adjusted by those skilled in the art. The effective dose can be determined using conventional techniques and by observing results obtained under similar conditions. The therapeutically effective dose of the prodrug of the present invention will vary depending on the infectious disease to be treated or prevented, the severity of the infectious disease to be treated, the route of administration, any co-treatments involved, the patient's age, weight, overall medical condition, medical history, etc. Typically, the amount of prodrug administered to the patient can range from about 0.001 mg / day / kg to 100 mg / day / kg body weight, preferably from 0.1 mg / day / kg to 25 mg / day / kg body weight, and more preferably from 0.1 mg / day / kg to 10 mg / day / kg body weight.

[0205] The prodrug of the present invention can be administered at least once a day for several days, weeks or months until the desired therapeutic effect is achieved.

[0206] The prodrugs of this invention can be administered topically, parenterally, or enterally. In fact, the prodrugs of this invention can be administered via any conventional route, including but not limited to oral, buccal, sublingual, rectal, intravenous, intramuscular, subcutaneous, intraosseous, dermal, transdermal, mucosal, transmucosal, intra-articular, intracardiac, intracerebral, intraperitoneal, intranasal, pulmonary, intraocular, vaginal, or transdermal routes. Furthermore, the route of administration of the prodrugs of this invention can vary depending on the infectious disease being treated and the patient's organs or tissues affected by the disease.

[0207] In some preferred embodiments, the prodrug of the present invention is administered via an intravenous or oral route.

[0208] - The pharmaceutical composition of the present invention

[0209] On the other hand, the present invention relates to a pharmaceutical composition comprising:

[0210] (i) a prodrug of formula (A), (A1), (A2) or (A3) and any of the above as an active ingredient (or a pharmaceutically acceptable salt or solvate thereof), and (ii) at least one pharmaceutically acceptable excipient.

[0211] The pharmaceutical composition of the present invention may comprise:

[0212] - 0.01% to 90% by weight of the prodrug of the present invention, and

[0213] - 10% to 99.99% excipients by weight,

[0214] The percentage is expressed as a percentage of the total weight of the composition.

[0215] Preferably, the pharmaceutical composition may comprise:

[0216] - 0.1% to 50% by weight of the prodrug of the present invention, and

[0217] - 50% to 99.9% excipients by weight.

[0218] This pharmaceutical composition is preferably used for the treatment or prevention of infectious diseases caused by fungi such as Candida, Aspergillus, and Cryptococcus species or protozoa such as Leishmania.

[0219] The pharmaceutical compositions of the present invention can be formulated according to standard methods, such as those described in Remington: The Science and Practice of Pharmacy (Lippincott Williams & Wilkins; 21st edition, 2005).

[0220] The pharmaceutically acceptable excipients that can be used are specifically described in the *Handbook of Pharmaceuticals Excipients*, American Pharmaceutical Association (Pharmaceutical Press; 6th revised edition, 2009). Generally, the pharmaceutical compositions of the present invention can be obtained by mixing the prodrug of the present invention with at least one pharmaceutical excipient.

[0221] Examples of suitable excipients include, but are not limited to, solvents such as water or water / ethanol mixtures, fillers, carriers, diluents, binders, anti-caking agents, plasticizers, disintegrants, lubricants, flavoring agents, buffers, stabilizers, colorants, dyes, antioxidants, anti-adhesion agents, softeners, preservatives, surfactants, waxes, emulsifiers, wetting agents, and flow aids. Examples of diluents include, but are not limited to, microcrystalline cellulose, starch, modified starch, dicalcium phosphate dihydrate, calcium sulfate trihydrate, calcium sulfate dihydrate, calcium carbonate, monosaccharides or disaccharides such as lactose, dextrose, sucrose, mannitol, galactose and sorbitol, xylitol, and combinations thereof. Examples of binders include, but are not limited to, starches such as potato starch, wheat starch, corn starch, gums such as astragalus gum, gum arabic and gelatin, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, crosspovidone, polyethylene glycol, and combinations thereof. Examples of lubricants include, but are not limited to, fatty acids and their derivatives such as calcium stearate, glyceryl monostearate, glyceryl palmitate, magnesium stearate, zinc stearate, or stearic acid, or polyalkylene glycols such as PEG. Gliders may be selected from colloidal silica, silica, talc, etc. Examples of disintegrants include, but are not limited to, crospovidone, croscarmellose salts such as sodium croscarmellose, starch, and their derivatives. Examples of surfactants include, but are not limited to, silicone, triethanolamine, polysorbates, and their derivatives such as Tween. 20 or Tween 40. Poloxamer, fatty alcohols such as lauryl alcohol, cetyl alcohol, and alkyl sulfates such as sodium dodecyl sulfate (SDS). Examples of emulsifiers include fatty acid esters or mixtures of these substances, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, methyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide, oils, polyethylene glycol, and sorbitol.

[0222] Needless to say, the excipients to be combined with the prodrug of the present invention may vary depending on the following factors: (i) the physicochemical properties of the active prodrug, including stability, (ii) the pharmacokinetic profile required for the active ingredient, (iii) the dosage form, and (iv) the route of administration.

[0223] The pharmaceutical composition can be of any type. For example, the pharmaceutical composition can be a solid oral dosage form, a liquid oral dosage form, a suspension for, for example, intravenous administration, a dosage form for topical application such as creams, ointments, gels, etc., patches such as transdermal patches, mucosal adhesive patches or tablets, especially adhesive tape or bandages, suppositories, or aerosols for intranasal or pulmonary administration. The pharmaceutical composition can provide immediate, controlled, or prolonged release of the prodrug of the present invention. Oral solid dosage forms include, but are not limited to, tablets, capsules, pills, and granules. Optionally, the oral solid form can be prepared with a coating and a shell, such as enteric coating or other suitable coatings or shells. Several such coatings and / or shells are known in the art. Examples of coating compositions that can be used are polymeric substances and waxes. The prodrug can also be used in the form of microencapsulation, if suitable, with one or more of the above-described excipients. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. The liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, methyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide, oils, fatty acid esters of polyethylene glycol and sorbitol, or mixtures thereof. If desired, the composition may also include adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and / or aroma agents. The suspension may contain suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitol esters, microcrystalline cellulose, aluminum hydroxide, bentonite, agar, etc.

[0224] Vaginal or rectal suppositories can be prepared by mixing the prodrug of the present invention with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol, or a suppository that is solid at room temperature but liquid at body temperature, with a wax.

[0225] The ointments, pastes, creams, and gels may contain excipients such as oils, waxes, paraffin wax, starch, astragalus gum, cellulose derivatives, polyethylene glycol, silicone, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof. The pharmaceutical compositions may also be in the form of aerosols, which can be delivered to the lungs using an inhaler system. For example, the prodrug of the present invention may be adsorbed onto the surface of a nanocarrier or microcarrier.

[0226] In some embodiments, the pharmaceutical composition of the present invention is an injectable composition, such as a composition for injection, such as intramuscular injection, intravenous injection, or infusion.

[0227] Typically, the pharmaceutical composition may be in the form of a liquid composition that is ready for injection, a concentrated liquid composition that is diluted prior to injection, or a powder, such as a freeze-dried powder, that is dissolved or suspended in a suitable medium prior to administration to the subject.

[0228] The prodrug of the present invention can be formulated into liposome compositions, lipid complex compositions, for example by using excipients such as phospholipids, cholesterol, etc., lipid complexes, or colloidal dispersions, for example by using surfactants and / or lipids, for example in... or Surfactants and / or lipids present in the formulation.

[0229] The present invention also relates to a kit comprising a prodrug of the present invention or a pharmaceutical composition of the present invention, and combined with means for administration to a subject, such as a reconstitution buffer, and / or means for injection, such as a needle and syringe. The kit may also include instructions for practicing the treatment methods of the present invention.

[0230] Other aspects and advantages of the invention will be disclosed in the experimental section below, which should be regarded as illustrative and does not limit the scope of this application.

[0231] Example

[0232] All reagents, including enzyme samples, were purchased from various commercial suppliers (Sigma). Alfa or TCI Store according to the instruction manual. The following solvents and reagents are freshly distilled under argon before use: DCM, MeCN, and Et3N on anhydrous calcium hydride; MeOH on sodium; and THF on sodium and benzophenone. DCM is sometimes also purified using a solvent purification system (SPS). Anhydrous DMF is available from Sigma. If necessary, the solvents used for separation, purification, and refining are distilled beforehand on a Buchi R-220-SE rotary evaporator to remove stabilizers.

[0233] Example 1: Synthesis of the prodrug of the present invention

[0234] according to Figure 2 The synthesis process described in the article prepares Figure 1A The AmB prodrug was obtained in a 6-step sequence with a total yield of 58% after optimizing the reaction conditions. Figure 2 The synthesis scheme is described below.

[0235] Compound 6

[0236]

[0237] In a sealed tube, commercially available N-acetyl-D-glucosamine (3.000 g, 13.50 mmol, 1.0 eq) was dissolved in freshly prepared HCl. g The gas was dissolved in a saturated solution of acetyl chloride (15 mL, 210.2 mmol, 9.3 eq), and the solution was cooled to 0 °C. The reaction mixture was heated and stirred at room temperature for 7 days. After completion, the reaction mixture was dissolved in DCM (20 mL) and cooled to 0 °C. The organic layer was carefully washed with saturated aqueous NaHCO3 solution (3 x 30 mL) and brine (30 mL). The organic layer was separated, dried on Na2SO4, filtered, and evaporated under reduced pressure. The crude product was purified by rapid column chromatography on silica gel (gradient elution 100:0 to 0:100 DCM / EtOAc) to give compound 6 (3.305 g, 67%) as an air-sensitive white solid.

[0238] 1 H NMR (300.13MHz, CDCl3, 298.15K): δ H 6.19(d,J 1-2 =3.6Hz, 1H, H 1 ),5.79(d,J 7-2 =8.7Hz, 1H, H 7 ),5.30(m,1H,H 3 ),5.22(t,J 4-3,4-5 =9.6Hz, 1H, H 4 ), 4.57-4.50(m,1H,H) 2 ), 4.32-4.24(m,2H,H 5 H 6a ),4.14(m,1H,H 6b ),2.11(s,3H,H 乙酰基 ),2.06(s,3H,H 乙酰基 ),2.05(s,3H,H 乙酰基 ),1.99(s,3H,H 乙酰基 ppm.

[0239] 13 C NMR (75.48MHz, CDCl3, 298.15K): δ C 171.5(s,C 乙酰基 ),170.6(s,C 乙酰基 ),170.2(s,C 乙酰基 ),169.2(s,C 乙酰基),93.6(s,C 1 ),70.9(s,C 5 ),70.1(s,C 3 ),66.9(s,C 4 ),61.1(s,C 6 ),53.5(s,C 2 ),23.1(s,C 乙酰基 ),21.5(s,C 乙酰基 ),20.7(s,C 乙酰基 ),20.6(s,C 乙酰基 ppm.

[0240]

[0241]

[0242] Compound 7

[0243]

[0244] The commercially available compound 4-hydroxy-3-nitrobenzaldehyde (1.372 g, 8.21 mmol, 1.5 eq) was dissolved in freshly distilled MeCN (40 mL). Activated molecular sieves were added at room temperature. Compound 6 (1.000 g) and Ag₂O (2.535 g, 10.94 mmol, 2.0 eq) were added. The reaction mixture was stirred for 15 min at room temperature and under a positive pressure argon atmosphere. Compound 6 (2.000 g, 5.47 mmol, 1.0 eq) was added. The reaction mixture was stirred in the dark at room temperature and under a positive pressure argon atmosphere and monitored by TLC (EtOAc, with UV). 254 nm / Cerium molybdate revealed). After completion, the reaction mixture was filtered on a diatomaceous earth pad, the residue was washed with DCM, and the organic layer was evaporated under reduced pressure. The crude product was purified by rapid column chromatography on silica gel (gradient elution 100:0 to 0:100 DCM / EtOAc) to give compound 7 as a white solid (3.720 g, quantified).

[0245] 1 H NMR (300.13MHz, CDCl3, 298.15K): δ H 9.97(s, 1H, H) 14 ),8.29(s,1H,H 10 ),8.05(dd,J 12-10 =2.0Hz, J 12-13 =8.2Hz, 1H, H 12), 7.49 (d, J 13-12 = 8.2 Hz, 1H, H 13 ), 5.94 (d, J 7-2 = 6.5 Hz, 1H, H 7 ), 5.81 (d, J 1-2 = 7.5 Hz, 1H, H 1 ), 5.70 (t, J 3-2,3-4 = 9.6 Hz, 1H, H 3 ), 5.13 (t, J 4-3,4-5 = 9.2 Hz, 1H, H 4 ), 4.34 - 3.17 (m, 2H, H 5 , H 6a ), 4.00 (m, 1H, H 6b ), 3.82 (m, 1H, H 2 ), 2.10 (s, 3H, H 乙酰基 ), 2.07 (s, 3H, H 乙酰基 ), 2.06 (s, 3H, H 乙酰基 ), 1.97 (s, 3H, H 乙酰基 ) ppm.

[0246] 13 C NMR (75.48 MHz, CDCl3, 298.15 K): δ C 188.7 (s, C 14 ), 171.3 (s, C 乙酰基 ), 170.6 (s, C 乙酰基 ), 170.4 (s, C 乙酰基 ), 169.6 (s, C 乙酰基 ), 153.8 (s, C 8 ), 141.4 (s, C 9 ), 134.4 (s, C 12 ), 131.5 (s, C 11 ), 126.8 (s, C 10 ), 119.5 (s, C 13 ), 98.6 (s, C 1 ), 72.6 (s, C 5 ), 70.7 (s, C 3 ), 68.5 (s, C 4 ), 62.0 (s, C 6 ), 55.7 (s, C 2 ), 23.4 (s, C 乙酰基 ), 20.8 (overlapped, C 乙酰基 , C 乙酰基 , C 乙酰基,)ppm.

[0247]

[0248] Compound 8

[0249]

[0250] Compound 7 (4.719 g, 9.51 mmol, 1.0 eq) was dissolved in a mixture of CHCl3 (74 mL), i-PrOH (21 mL), and silica gel (7.608 g), and the solution was cooled to 0 °C. NaBH4 (1.079 g, 28.53 mmol, 3.0 eq) was added, and the reaction mixture was stirred for 15 min at 0 °C under a positive pressure argon atmosphere. The reaction mixture was then heated and stirred for 10 h at room temperature under a positive pressure argon atmosphere, and the reaction mixture was monitored by TLC (EtOAc, with UV). 254 nm (Cerium molybdate revealed). After completion, the reaction mixture was cooled to 0°C. The organic layer was carefully washed with 1.0 M HCl solution (15 mL) and brine (30 mL). The organic layer was separated, dried on Na2SO4, filtered, and evaporated under reduced pressure, giving compound 8 as a white solid (5.055 g, quantitative).

[0251] 1 H NMR (300.13MHz, CDCl3, 298.15K): δ H 7.78(d,J 10-12 =2.1Hz, 1H, H 10 ),7.46(dd,J 12-10 =2.1Hz, J 12-13 =8.6Hz, 1H, H 12 ),7.35(d,J 13-12 =8.5Hz, 1H, H 13 ),5.85(d,J 7-2 =8.2Hz, 1H, H 7 ),5.55(dd,J 3-2,3-4 =9.2,10.4Hz,1H,H 3 ),5.45(d,J 1-2 =8.2Hz, 1H, H 1 ),5.12(t,J 4-3,4-5 =9.5Hz, 1H, H 4 ),4.71(s,2H,H 14 ),4.27(dd,J 6a-5 =5.2Hz,J 6a-6b =12.3Hz, 1H, H6a ),4.20(dd,J 6b-5 =2.7Hz,J 6b-6a =12.2Hz,1H,H 6b ),3.93(dt,J 2-1,2-3,2-7 =8.1,10.4Hz,1H,H 2 ),3.86(m,1H,H 5 ),2.67(s,1H,H 15 ),2.09(s,3H,H 乙酰基 ),2.06(s,3H,H 乙酰基 ),2.04(s,3H,H 乙酰基 ),1.98(s,3H,H 乙酰基 )ppm.

[0252] 13 C NMR(75.48MHz,CDCl3,298.15K):δ C 171.3(s,C 乙酰基 ),170.7(s,C 乙酰基 ),170.6(s,C 乙酰基 ),169.6(s,C 乙酰基 ),148.5(s,C 8 ),141.8(s,C 9 ),137.6(s,C 11 ),132.0(s,C 12 ),123.0(s,C 10 ),121.5(s,C 13 ),100.0(s,C 1 ),72.4(s,C 5 ),71.5(s,C 3 ),68.8(s,C 4 ),63.6(s,C 14 ),62.1(s,C 6 ),55.4(s,C 2 ),23.4(s,C 乙酰基 ),20.9(s,C 乙酰基 ),20.8(s,C 乙酰基 ),20.8(s,C 乙酰基 )ppm.

[0253]

[0254] Compound 9

[0255]

[0256] Compound 8 (1.317 g, 2.64 mmol, 1.0 eq) was dissolved in freshly distilled MeCN (20 mL). Et3N (440 μL, 3.17 mmol, 1.2 eq) and commercially available N,N'-disuccinimidyl carbonate (743 mg, 2.90 mmol, 1.1 eq) were added. The reaction mixture was stirred for 24 h at room temperature under a positive pressure argon atmosphere and monitored by TLC (EtOAc, with UV). 254nm (Cerium molybdate revealed). After completion, the organic layer was evaporated under reduced pressure, giving crude product 9 as a highly air-sensitive yellow solid, which was immediately used in subsequent steps due to its instability. For further characterization, a batch of crude product was purified by rapid column chromatography on silica gel (gradient elution 100:0 to 0:100 DCM / EtOAc) to give pure compound 9 as a highly air-sensitive white solid.

[0257] 1 H NMR (300.13MHz, CDCl3, 298.15K): δ H 7.82(s, 1H, H) 10 ),7.57(d,J 12-13 =8.5Hz, 1H, H 12 ),7.40(d,J 13-12 =8.4Hz, 1H, H 13 ),6.58(d,J 7-2 =8.2Hz, 1H, H 7 ),5.56(d,J 1-2 =9.0Hz,1H,H 1 ), 5.49 (d, J = 10.1 Hz, 1H, H 3 ),5.28(s,2H,H 14 ),5.10(t,J 4-3,4-5 =9.5Hz, 1H, H 4 ), 4.32-4.15(m,2H,H 6a H 6b ), 4.04-3.92(m,2H,H 2 H 5 ),2.84(s,4H,H 17 ),2.08(s,3H,H 乙酰基 ),2.03(s,6H,H 乙酰基 ),1.95(s,1H,H 乙酰基 ppm.

[0258] 13C NMR (75.48MHz, CDCl3, 298.15K): δ C 172.7(s,C 乙酰基 ),170.9(s,C 乙酰基 ),169.7(s,C 乙酰基 ),168.9(s,C 16 ),151.5(s,C 15 ),150.1(s,C 8 ),141.0(s,C 9 ),134.2(s,C 12 ),129.1(s,C 11 ),125.6(s,C 10 ),120.3(s,C 13 ),99.2(s,C 1 ),72.2(s,C 5 ),71.3(s,C 3 ),70.8(s,C 14 ),68.6(s,C 4 ),62.0(s,C 6 ),55.0(s,C 2 ),25.5(s,C 17 ),23.0(s,C 乙酰基 ),20.9(s,C 乙酰基 ),20.8(s,C 乙酰基 ppm.

[0259]

[0260] Compound 10

[0261]

[0262] Crude compound 9 (1.040 g, 1.25 mmol, 5.0 eq) was dissolved in anhydrous DMF (5 mL), and the solution was stirred for 15 min at room temperature under a positive pressure argon atmosphere. Commercially available compounds amphotericin B (231 mg, 0.25 mmol, 1.0 eq) and Et3N (77 μL, 0.55 mmol, 2.2 eq) were added. The reaction mixture was stirred at room temperature in the dark for 23 h and monitored by reversed-phase TLC (15:85 H2O / an organic mixture consisting of 43:20 MeOH / MeCN, measured using UV). 254nm(Cerium molybdate revealed). After completion, the reaction mixture was co-evaporated with toluene. The crude product was dissolved in toluene under sonication and placed at –18°C. The precipitate was filtered, washed with DCM, and dried under reduced pressure to give compound 10 (312 mg, 86%) as a brown solid.

[0263] 1 H NMR (300.13MHz, 2:1DMSO-d6 / MeOD, 298.15K): δ H 7.81 (d, J = 1.7 Hz, 1H, H) 9 ), 7.67-7.58(m,1H,H) 11 ), 7.41(d, J = 8.7 Hz, 1H, H 12 ), 7.23-7.05(m,2H,H 7 H 7’ ), 6.51-5.83(m,12H,H 21” to H 32” ), 5.47-5.32(m,2H,H 1 H 33” ),5.28-5.13(m,2H,H 37” H 4 ),5.02(s,2H,H 13 ), 4.95(t, J = 9.5 Hz, 1H, H 5 ), 4.45-4.35(m,2H,H 1’ H 3 ), 4.35-3.92(m,9H,H 2 H 6a H 6b H 5’ H 3” H 11” H 15” H 17” H 19” ,),3.65-3.51(m,2H,H 2’ H 5” ), 3.51-3.36(m,2H,H 3’ H 4’ ),3.26-3.12(m,2H,H 8” H 9” ), 3.12-2.99(m,1H,H) 35” ),2.36-2.24(m,1H,H 34” ),2.24-2.06(m,2H,H 2” ), 2.00 (overlap, 4H, H) 乙酰基 H16” ),1.96(s,3H,H 乙酰基 ),1.91(s,3H,H 乙酰基 ),1.78(s,3H,H 乙酰基 ),1.75-1.18(m,15H,H 4” ,H 6” ,H 7” ,H 10” ,H 12” ,H 14” ,H 18” ,H 36” ),1.16(d,J=5.5Hz,3H,H 6’ ),1.10(d,J=6.3Hz,3H,H 38” ),1.02(d,J=6.2Hz,3H,H 40” ),0.90(d,J=7.1Hz,3H,H 39” )ppm.

[0264] 13 C NMR(75.48MHz MHz,2:1DMSO-d6 / MeOD,298.15K):δ C 171.4(s,C 1” ),170.8(s,C 乙酰基 ),170.7(s,C 乙酰基 ),170.4(s,C 乙酰基 ),169.9(s,C 乙酰基 ),156.5(s,C 14 ),148.9(s,C 7 ),141.2(s,C 8 ),124.2(s,C 9 ),137.2(s,C 33” ),137.1(s,C 乙烯 ),134.4(s,C 乙烯 ),134.3(s,C 乙烯 ),133.9(s,C 乙烯 ),133.8(s,C 乙烯 ),133.6(s,C 11 ),133.2(m,C 10 ,C 乙烯 ),133.0(s,C 乙烯 ),132.9(s,C 乙烯 ),132.7(s,C 乙烯 ),132.6(s,C 乙烯 ),132.0(m,C乙烯 C 乙烯 ),129.6(s,C 乙烯 ),118.3(s,C 12 ),99.5(s,C 1 ),97.9(s,C 11” ),97.5(s,C 1’ ),78.0(s,C 35” ),75.7(s,C 3 ),74.9(s,C 4’ ),74.3(s,C 19” ),72.7(s,C 4 ),72.1(s,C 5’ ), 70.6 (overlap, C 5” C 8” C 9” C 11” ),69.9(s,C 2’ ),69.7(s,C 37” ),67.4(s,C 3” ), 66.1 (overlap, C 15” C 17” ),64.4(s,C 13 ),62.1(s,C 6 ), 57.5 (overlap, C 3’ C 16” ),53.7(s,C 2 ),46.8(s,C 14” ), 44.7 (overlap, C 4” C 10” C 12” ),43.2(s,C 34” ),42.4(s,C 2” ),36.1(s,C 18” ), 35.6 (overlap, C 6” C 7” C 18” ),22.6(s,C 乙酰基 ),20.6(s,C 乙酰基 ),20.4(s,C 乙酰基 ),20.4(s,C 乙酰基 ),18.8(s,C 40” ),18.3(s,C 6’ ),17.1(s,C 38” ),12.3(s,C 39” ppm.

[0265] In this 13In C10 NMR assignment, some atoms are not assigned a class. (This corresponds to C10 NMR.) 36” The carbon signal overlaps with the DMSO-d6 signal.

[0266]

[0267] mp: 155℃

[0268] Yield: 86%

[0269] Compound 1 (prodrug)

[0270]

[0271]

[0272] Composed of 43:20MeOH / MeCN

[0273] (organic mixture)

[0274] mp = 164℃ (decomposition)

[0275] Yield: Quantitative

[0276] Compound 10 (259 mg, 0.18 mmol, 1.0 eq) was dissolved in a mixture of freshly distilled MeOH (1.8 mL) and THF (720 μL), and the solution was stirred for 15 min at room temperature under a positive pressure argon atmosphere. K₂CO₃ (124 mg, 0.90 mmol, 5.0 eq) was added. The reaction mixture was stirred at room temperature in the dark for 22 h and monitored by reversed-phase TLC (15:85 H₂O / an organic mixture consisting of 43:20 MeOH / MeCN, with UV...). 254nm (Cerium molybdate revealed). After completion, sulfonic acid resin was added, and the reaction mixture was stirred at room temperature for 15 min. The reaction mixture was filtered, the resin was thoroughly washed with MeOH, and the organic layer was evaporated under reduced pressure to give compound 11 as an orange solid (298 mg, quantified). Further purification was performed on preparative LC if necessary.

[0277] 1 H NMR (300.13MHz, 2:1DMSO-d6 / CD3OD, 298.15K): δ H7.82(br,1H),7.76(d,J=8.9Hz,1H),7.62(d,J=8.9Hz,1H),7.43(d,J=8.9Hz,1H),7.29-7.10(m,1H),7.88(d,J=8 .9Hz,1H),6.53-6.20(m,10H),6.20-6.01(m,4H),5.99-5.84(m,2H),5.49-5.39(m,1H),5.38-5.31(m,1H),5.25-5 .14(m,2H),5.12-5.07(m,1H),5.04-4.99(s,1H),4.83-4.73(m,3H),4.68-4.61(m,2H),4.48-4.36(m,3H),4.27-4 .17(m,2H),4.11-3.99(m,2H),2.75-2.70(m,1H),2.32-2.24(m,2H),2.19-2.14(m,1H),2.08(s,1H),1.78(s,3H,H 乙酰基 ),1.75-1.18(m,15H),1.15(d,J=5.5Hz,3H),1.11(d,J=6.2Hz,3H),1.03(d,J=5.8Hz,3H),0.91(d,J=6.9Hz,3H)ppm.

[0278] Example 2: Evaluation of AmB prodrugs

[0279] -Materials and methods

[0280] Enzymatic release and aqueous solution stability

[0281] In vitro enzymatic hydrolysis was performed using commercially available β-N-acetylhexosaminease EC3.2.1.52 (22.8 units / mg) derived from canavalia ensiformis. -1 Proteins were used in a suspension in 2.5M ammonium sulfate (pH 7.0) for analysis. Cooling Thermal Shake Touch, and monitoring by LC analysis. Incubate prodrug 1 with the enzyme according to the table below.

[0282]

[0283] Table 1: Conditions for Enzyme-Activated Assay

[0284] Antifungal and antiparasitic activities (in vitro)

[0285] The half-maximum inhibitory concentration (IC50) required to inhibit 50% of in vitro cell growth or survival. 50The susceptibility was determined using the microdilution method of culture medium, according to the recommendations of the European Commission for antimicrobial susceptibility testing (Protocol E.DEF 7.3.1 for Candida species) and the certified internal procedures of the laboratory IICiMed (for Leishmania species) (LePape et al., Acta Parasitologica 2002, 47, 79-81).

[0286] The different strains, isolates, and cell lines used are listed below:

[0287] -Candida albicans clinical strain (IICiMed number CAAL93)

[0288] -Clinical strain of Candida albicans (IICiMed number CAAL121)

[0289] -Candida albicans reference strain SC5314 (IICiMed number CAAL146)

[0290] - Reference strain MHOM / IL / 81 / BNI (IICiMed number LEMA1) of Leishmania major

[0291] -A549 reference cell line CCL-185 (lung cancer epithelial cells)

[0292] -HeLa reference cell line

[0293] Growth or cell viability was assessed on flat-bottomed microplates, initially by visual observation and always confirmed by measuring absorbance at 595 nm using a Bio-Rad iMark microplate absorbance reader, or by measuring fluorescence at 590 nm after excitation at 530 nm using a Packard fluorocount microplate reader BF10000 with a halogen lamp source, according to the resazurin cell viability assay. Results represent the average (± standard error of the average SEM, if available) calculated from at least two independent experiments, each performed in triplicate on one or more strains. Values ​​are expressed in μM, relative to the corresponding pathogen.

[0294] result

[0295] -Enzyme release assessment

[0296] The release of AmB from prodrug 1 was confirmed by incubating it with the enzyme of interest. Therefore, real-time monitoring allowed for observation of the release kinetics in the presence of the enzyme of interest and its good aqueous stability in the absence of the enzyme. The release kinetics are shown in… Figure 3 middle.

[0297] -In vitro cell assessment

[0298] The prodrug was tested on different cell types, budding spores or filamentous yeasts, to determine antifungal activity; on Leishmania proflagellates and intracellular aflagellates to determine antiprotozoan activity; and finally, on human cells to detect cytotoxicity. The results are shown in Table 2 below:

[0299]

[0300]

[0301] Table 2 – Antifungal and antiparasitic activities compared to cytotoxicity in human cells (*morphological changes observed at 10 μM)

[0302] Compound 1 showed similar activity levels to amphotericin B against *Candida albicans* and *Leishmania macrophylla*. Compound 1 also showed activity against *Cryptococcus neoformans* and *Cryptococcus gattii*. Notably, compound 1 exhibited low toxicity to HeLa cells. Furthermore, compound 1 did not show toxicity to the lung cell line A549 or human PBMCs (CI). 50 >50μM).

[0303] Example 3: Evaluation of the antifungal activity of AmB prodrugs in vivo

[0304] ·Materials and methods

[0305] Immunosuppression was achieved in mice by subcutaneous injection of 30 mg / kg prednisolone one day prior to irritation. On day 0, mice were intravenously infected with Candida albicans bud conidia. One hour post-infection, mice were administered 1 mg / kg body weight once daily for three consecutive days. and AmB prodrug (compound 1, Figure 1A Intraperitoneal treatment was administered. The control group received sterile distilled water (the medium). Survival rates were monitored for 14 days post-inoculation. Differences between groups were analyzed using a log-rank test.

[0306] On day 14, all mice were euthanized, their kidneys were removed and weighed.

[0307] Tissue homogenates were serially diluted 10 to 1000 times in sterile saline, then plated on Sabouraud dextrose agar and incubated for 48 h to determine the number of CFUs. Tissue fungal load was expressed as the log-mean of CFU / g tissue. Differences in mean CFU in the kidneys were compared to the mediator control using one-way ANOVA and post-hoc Tukey's test. A p-value <0.05 was considered statistically significant.

[0308] ·result

[0309] Figure 1 shows the mice treated with the vector died before day 5. All treatments ( (Amphotericin B) (AmB in the liposome composition) and the AmB prodrug of the present invention (in) Figure 4A and 4B The drug (referred to as GOG) statistically improved survival (p>0.001). No statistical difference was observed between the treatments used. Regarding fungal load in the kidneys, mice treated with the AmB prodrug showed a significant reduction in load compared to the placebo-treated control group (p<0.0079). No significant difference was measured between the treatments used (p>0.05). In other words, these data show that the AmB prodrug of the present invention is at least as effective as the AmB drug.

[0310] Example 4: Evaluation of AmB prodrugs in a Galleria mellonella model

[0311] • Assess toxicity in the Galleria mellonella model.

[0312] The larval model represents a rapid and practical tool for assessing the inherent toxicity of active substances. For further details on the model, see Le Pape et al., 2019, Int J Infect Dis. 2019 Apr; 81:85-90. The larvae were incubated with AmB, the AmB prodrug (compound 1), and the carrier. Results regarding toxicity are shown in... Figure 5A In 2 mg / kg -1 At the specified dose, AmB was highly toxic, resulting in a 40% survival rate in the treatment group. In contrast, at equivalent doses, its prodrug form was significantly less toxic, with a survival rate of 80%. This statistically significant difference was confirmed by in vitro results on human cells and demonstrates reduced toxicity of AmB in its carbamate prodrug form.

[0313] • Evaluate in vivo anti-cryptococcal activity in the Galleria mellonella model

[0314] This model also constitutes a screening model and is a good alternative to traditional studies on mouse models used to assess the activity of antifungal molecules. The antifungal efficacy of the AmB prodrug of the present invention (compound 1) against *Cryptococcus neoformans* and *Cr. gattii* was evaluated. Figure 5B Survival curves of the large wax moth (G. mellonella) infected with *Cryptococcus neoformans* and treated with amphotericin B or its N-acetyl-D-glucosamine procarbamate are shown. Without treatment, all larvae died after 6 and 5 days, respectively. For *Cryptococcus neoformans*, at 2 mg / kg... -1 At the dose of amphotericin B, amphotericin B resulted in a 50% survival rate, and its prodrug was also effective, with a survival rate of 30% at equivalent doses.

[0315] In the case of Cryptococcus gattii, amphotericin B and the prodrug resulted in survival rates of 30% and 20%, respectively.

Claims

1. An antifungal prodrug of the following formula: Or its medicinal salt.

2. The antifungal prodrug according to claim 1, used for the treatment or prevention of infectious diseases.

3. The antifungal prodrug according to claim 2, wherein the infectious disease is caused by a fungal infection belonging to the genus *Candida* (…). Candida Aspergillus ( ) Aspergillus Cryptococcus genus ( Cryptococcus ), Mucorales ( Mucorales Fusarium ( ) Fusarium ), genus Blastomyces ( Blastomyces ), Mucorales ( Mucorales ) or Leishmania ( Leishmania Caused by pathogens of the species.

4. The antifungal prodrug of claim 2, used for the treatment or prevention of invasive fungal diseases in immunocompromised subjects.

5. A pharmaceutical composition comprising the antifungal prodrug according to claim 1 and a pharmaceutically acceptable excipient.

6. Use of the antifungal prodrug as defined in claim 1 in the preparation of a medicament for treating or preventing infectious diseases in a subject.

7. The use according to claim 6, wherein the infectious disease is caused by a pathogen belonging to the genera *Candida*, *Aspergillus*, *Cryptococcus*, *Mucorales*, *Fusarium*, *Blastomyces*, *Mucorales*, or *Leishmania*.

8. The use according to claim 6, wherein the drug is used to treat or prevent fungal diseases in immunocompromised subjects.

9. The use according to claim 6, wherein the drug is suitable for administration via oral or intravenous route.

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